Chronic pain, especially postoperative pain, is a common clinical symptom, involving diseases including various clinical diseases, may produce a series of pathophysiological changes while making the patient feel painful, such as affecting the body's autonomic nervous system, resulting in an accelerated heart rate, hard and jerky breath, and risen blood pressure; affecting the mood, resulting in dysphoria and depression, followed by affecting the digestive system function and physical recovery; affecting the endocrine and hormone levels, disrupting the body's internal environment directly and indirectly. Therefore, a reasonable analgesia should play the role of: (1) alleviating the sufferer's pain and discomfort, relieving anxiety, and improving sleep; allowing the patient to pass the postoperative stage in a more comfortable state; (2) eliminating symptoms of not wishing to breathe deeply and coughing caused by pain, improving breathing, promoting sputum excretion, reducing lung infection; (3) alleviating pain, promoting patients to leave bed and move early, early functional exercise, reducing the risk of deep venous thrombosis caused by staying in bed for long periods of time; (4) blocking the sympathetic overexcitation, eliminating tension, expanding the blood vessel, improving the microcirculation, thereby promoting wound healing, and speeding up the postoperative recovery; (5) inhibiting sympathetic activity, promoting gastrointestinal motility, helping restore gastrointestinal function after surgery; and, (6) shortening the hospitalization time and saving the cost by reducing the complications and accelerating the rehabilitation.
Many primary symptoms of chronic pain are not easy to be eliminated, and the pain symptoms caused by them are mostly treated by symptomatic treatment. Local block therapy is usually used, especially local anesthetic is used. They can temporarily block the nerve conduction completely and reversibly within the limited range of the human body, that is, make a certain part of the human body loss sensibility without the disappearance of consciousness, and thus play a role in relieving pain. For example, bupivacaine may be used alone or in combination with fentanyl or morphine for postoperative patient controlled epidural analgesia.
Local anesthesia is commonly used in clinical anesthesia, which is conducive to keeping the patient awake, smooth recovery of anesthesia, and easy postoperative analgesia. According to the structure type, local anesthetics can be divided into p-aminobenzoates, amides, aminoketones, amino ethers, and carbamates. The commonly used drugs are lidocaine, prilocaine, bupivacaine and ropivacaine, etc. In general, the local anesthetic has an activity sufficient to relieve certain pain, however the duration thereof is not long enough, and the patients are more likely to consistently input a low concentration of local anesthetic, to block only pain nerve without affecting the motor nerve, so as to achieve the goal of only playing analgesic effect without affecting the movement. Therefore, a sustained-release and long-acting local anesthetic is an ideal choice. Structural modification of the original local anesthetics is a way to prolong the duration of local anesthesia. E.g., bupivacaine has a structure similar to lidocaine, effect of local anesthesia stronger than that of lidocaine, and longer duration; L-bupivacaine is a new long-acting local anesthetic, as an isomer of bupivacaine, has a relatively low toxicity. Ropivacaine is structurally similar to bupivacaine, has a stronger effect for blocking the pain and has a weaker effect on exercise. In recent years, the development of peripheral nerve block technology and local anesthetic provides patients with more ideal and effective method of perioperative analgesia, usually combined with opioids, which can reduce the amount of opioids. Local anesthetics of amides such as bupivacaine, L-bupivacaine and ropivacaine are widely used in regional analgesia, especially ropivacaine, has the characteristics of separated blockade of sensory and motor, making them the preferred drug for regional analgesia. However, the duration of these drugs is still too low for the treatment of postoperative analgesia or chronic pain, e.g., the duration of lidocaine is 1-2 h, the duration of ropivacaine is 4.4 h, and even the duration of L-bupivacaine which is a long-acting local anesthetic is only 5-7 h.
Several sustained-release formulations of local anesthetic developed at present have been reported, e.g., polymer microspheres of polylactic acid combined with glycolic acid containing bupivacaine and dexamethasone can produce local anesthesia effect with long duration. The crystals of local anesthetics have also been shown to have a long duration. Lipophilic bupivacaine free radicals are incorporated into a multilayer liposomal cell membrane, and proton-gradient-loaded huge monolayer liposomes have been shown to last for 6-11 h. Multivesicular liposomes are being developed as a lipid-based topical or systemic slow-release drug. In November 2011, the FDA approved the Exparel, 1.3% liposome suspension for injection of bupivacaine developed by Pacira Pharmaceutical Co., Ltd., which was used for direct injection to the surgical site to help control postoperative pain. Bupivacaine is a non-opioid anesthetic, its conventional injection (0.5%) can only provide analgesic effect for less than 7 h, and postoperative pain may often last 48-72 h and is the most difficult to control in this time, so now a built-in catheter or infusion pump is usually used for continuous administration of opioids, resulting in management inconvenience and a variety of harmful side effects which may appear. By contrast, a single dose of Exparel can produce a significant analgesic effect up to 72 h after being injected into the surgical site, and thus reduce opioid dosage, which can be regarded as an important progress of postoperative pain management.